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immunosuppression following allografts may be regeneration in rat sciatic nerve transplantation model
discontinued after a period of treatment after nerve demonstrated significant re‑myelination and regeneration
regeneration becomes present. Allografts can also be of the transected and transplanted nerve. Tacrolimus
[14]
[22]
processed in such a way as to reduce their antigenicity was also shown to enhance nerve repair following nerve
by means of decellularization, although nerve growth crush injury in sciatic nerves in rats as compared to
can suffer from lack of extracellular signaling cues. [12] cyclosporin A, which had no effect on the rate of axonal
regeneration. [23]
It has been shown that the cessation of immunosuppression
is necessary for replacement of donor Schwann cells in the With respect to Schwann cell migration, tacrolimus
allograft with those of the host. In a mouse model of sciatic administration after sciatic nerve allografts in mice
nerve allografts, a continuous postgrafting treatment demonstrated rapid host cell migration followed by a
with cyclosporin A maintained allograft association with slow replacement phase after 15 weeks (replacement of
donor Schwann cells until a “chronic rejection process” donor Schwann cells by those of the host). Controlled
prevailed. This led to clearance of donor Schwann cells withdrawal of tacrolimus in this period can accelerate
and subsequent replacement by host Schwann cells. the replacement process. Temporally controlling the
[24]
However, to most efficiently facilitate replacement onset of an acute rejection process either early (5 days
of donor Schwann cells with those of the host, a posttransplant) or late (8 weeks posttransplant) in the
temporary immunosuppressive regimen to gradually allow regenerative timeframe demonstrated differing degrees
for rejection, is recommended. This controlled rejection of repair. The group undergoing early rejection had a
[15]
process allows for a gradual replacement of Schwann cells significantly better functional recovery in innervated
such that the growing axons maintain associations with muscles than those undergoing late rejection. Interestingly,
endoneurial Schwann cells. If the replacement does not immunohistochemical staining for Schwann cells revealed
occur and an acute rejection process suddenly destroys no difference in staining intensity between late and
donor Schwann cells supporting host axonal growth, then early rejection groups, although neural fiber width was
the entire regenerative process may be compromised. decreased in late rejection rats, potentially due to impaired
myelination production from damaged Schwann cells. [25]
Outcomes following repair of mid‑level brachial plexus
injuries with cadaveric/living‑related donor nerve The use of tacrolimus in posttransplant immunosuppressive
allografts in eight patients revealed no complications regimens can enhance nerve regeneration and growth of
during or immediately after the operation. Postprocedure axon sprouts into donor tissue. Further work remains to
immunosuppression included basiliximab, tacrolimus, be done regarding elucidation of the exact mechanism
azathioprine, and co‑trimoxazole. Seven of these by which tacrolimus affects nerve regeneration, but
patients displayed return of motor and sensory function. outcomes data, so far, has been promising. A 3‑year
The eighth was noncompliant with the posttransplant follow‑up examination of motor recovery after hand
immunosuppressive regimen, leading to impaired motor transplant in a 47‑year‑old patient revealed a
and sensory regeneration. [16] “remarkable speed” of regeneration. The investigators
attribute this to the neurotrophic effects of tacrolimus
Tacrolimus (FK506) and note that regeneration is possible even after the
Tacrolimus represents the current backbone of conventional patient’s median and ulnar nerves had been severed for
immunosuppressive regimen in SOT. Surprisingly, its use 14 years prior to the operation and immunosuppressive
was also shown to have an enhanced effect on nerve regimen. However, studies comparing tacrolimus to
[26]
regeneration in a dose‑dependent, calcineurin‑independent other immunosuppressive modalities and their resulting
mechanism. This combination of effects makes this drug effects on nerve regeneration have not been conducted.
[17]
very appealing in the context of VCA. Tacrolimus sustains Promising results from animal models, applications
this effect with both systemic and local administrations. [18]
in crushed nerve injury models, Schwann cell studies,
Specific to applications in VCA, administration of tacrolimus and preliminary data from VCA point to tacrolimus
in a swine model of ulnar nerve grafting demonstrated being a key neurotrophic candidate along with its
doubling of nerve growth parameters (nerve density, mean well‑characterized immunosuppressive capacity.
fiber count) postautograft. In allografts, tacrolimus was A summary of recent and pertinent publications can be
necessary for posttransplant neuroregeneration, as the found in Table 1.
absence of the drug abolished regeneration altogether.
[19]
Early studies of reinnervation of hemifacial VCAs in rats Outcomes studies
revealed that immunosuppression provided by tacrolimus Due to the limited number of hand and face transplants,
coupled with nerve repair in the form of epineurial and the diversity of such patients, large sample size
neurorraphies was successful in developing and maintaining analyses of sensory and motor regeneration are
sensory reinnervation of the graft tissues. Tacrolimus challenging, and few have been performed (requiring the
[20]
used in an orthotopic rat hind limb transplant model was establishment of a patient database for longitudinal and
shown to enhance neural regeneration, further enhanced cross‑sectional outcomes monitoring). Many outcomes
when a bone marrow‑derived stem cell (BMSC) suspension studies look into specific or small sets of patients. For
was injected into the distal end of the injured nerve. example, patient JM, who underwent a partial face
[21]
Low dose tacrolimus (0.1 mg/kg/day) in peripheral nerve transplant at Brigham and Women’s Hospital in Boston

228 Plast Aesthet Res || Vol 2 || Issue 4 || Jul 15, 2015